during human retrovirus infection

NF-KBIReI transcription factors participate in the activation of numerous genes involved in im- mime regulation/inflammation including cytokines, cell surface receptors, adhesion molecules, and acute phase proteins. NF-KB activity is controlled by inhib- itory proteins, IKB5, that maintain the DNA-binding forms of NF-KB in an inactive state in the cytoplasm. Many viruses, including the human retroviruses HIV-1 and HTLV-1, also utilize the NF-KBIIKB pathway to their transcriptional advantage during viral infection. Our recent studies have focused on the IKBa inhib- itor and have characterized several protein interactions that modulate the functional activity of IKBa during human retrovirus infection. In this article, we sum- marize recent studies demonstrating that (1) chronic mv-i infection ofhuman myelomonoblastic PLB-985 cells leads to constitutive NF-KB activity, activated in part due to enhanced IKBa turnover and increased NF-KBIRe1 production; (2) HTLV-1 Tax protein phys- ically associates with the IKBa protein in vivo and in vitro and also mediates a 20- to 40-fold stimulation of NF-KB DNA binding activity mediated via an en- hancement of NF-KB dimer formation; (3) casein kinase II phosphorylates IKBa at multiple sites in the C-terminal PEST domain and regulates IKBa function; (4) transdominant forms of IKBa, mutated in critical Ser or Thr residues required for inducer-mediated (S32A,S36A) and/or constitutive phosphorylation block HIV LTR trans-activation and also effectively inhibit HIV-1 multiplication in a single cycle infection model; and (5) the amino-terminal 55aa ofIKBa (NIK) interacts with the human homologue of dynein light chain 1, a small 9-kDa human homologue of the dy- nein light chain protein involved in microtubule and cytoskeletal dynamics. Together, our results highlight a number of intriguing molecular interactions between IKBa and cellular or viral proteins that modulate tran- scription factor activity and nuclear-cytoplasmic flow of host proteins. J. Leukoc. Biol. 62: 82-92; 1997.

[1]  J. Hiscott,et al.  Human T Cell Leukemia Virus Type 1 Tax Protein Increases NF-κB Dimer Formation and Antagonizes the Inhibitory Activity of the IκBα Regulatory Protein , 1996 .

[2]  M. Wainberg,et al.  Chronic human immunodeficiency virus type 1 infection of myeloid cells disrupts the autoregulatory control of the NF-kappaB/Rel pathway via enhanced IkappaBalpha degradation , 1996, Journal of virology.

[3]  Michael R. Green,et al.  HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs , 1996, Current Biology.

[4]  R. Rousset,et al.  Effects on NF-κB1/p105 processing of the interaction between the HTLV-1 transactivator Tax and the proteasome , 1996, Nature.

[5]  S. Sun,et al.  Persistent activation of NF-kappa B/Rel by human T-cell leukemia virus type 1 tax involves degradation of I kappa B beta , 1996, Journal of virology.

[6]  J. Hiscott,et al.  Phosphorylation of IkappaBalpha in the C-terminal PEST domain by casein kinase II affects intrinsic protein stability , 1996, Molecular and cellular biology.

[7]  T. Maniatis,et al.  Site-Specific Phosphorylation of IκBα by a Novel Ubiquitination-Dependent Protein Kinase Activity , 1996, Cell.

[8]  G. Bren,et al.  Casein kinase II phosphorylates I kappa B alpha at S-283, S-289, S-293, and T-291 and is required for its degradation , 1996, Molecular and cellular biology.

[9]  A. Pardee,et al.  A Tat-induced auto-up-regulatory loop for superactivation of the human immunodeficiency virus type 1 promoter , 1995, Journal of virology.

[10]  T. Maniatis,et al.  Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  E M Schwarz,et al.  Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. , 1995, Genes & development.

[12]  E. Harhaj,et al.  Activation of NF-κB/Rel by Tax involves degradation of IκBα and is blocked by a proteasome inhibitor , 1995 .

[13]  M A Wainberg,et al.  Regulation of Human Immunodeficiency Virus Type 1 and Cytokine Gene Expression in Myeloid Cells by Nf-␬b/rel Transcription Factors , 2022 .

[14]  I. Verma,et al.  Constitutive phosphorylation of I kappa B alpha by casein kinase II. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Rosbash,et al.  Identification of a novel nuclear pore-associated protein as a functional target of the HIV-1 Rev protein in yeast , 1995, Cell.

[16]  B. Cullen,et al.  Identification of a novel cellular cofactor for the Rev/Rex class of retroviral regulatory proteins , 1995, Cell.

[17]  Michael R. Green,et al.  A human nucleoporin-like protein that specifically interacts with HIV Rev , 1995, Nature.

[18]  T. Maniatis,et al.  Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. , 1995, Genes & development.

[19]  U. Siebenlist,et al.  Evidence in Support of a Role for Human T-cell Leukemia Virus Type I Tax in Activating NF-B via Stimulation of Signaling Pathways(*) , 1995, The Journal of Biological Chemistry.

[20]  D. Thomas,et al.  Inducible nuclear expression of newly synthesized I kappa B alpha negatively regulates DNA-binding and transcriptional activities of NF-kappa B , 1995, Molecular and cellular biology.

[21]  T. McKinsey,et al.  Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation , 1995, Molecular and cellular biology.

[22]  S. Gerstberger,et al.  Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation , 1995, Science.

[23]  M. Karin,et al.  Phosphorylation of I kappa B alpha precedes but is not sufficient for its dissociation from NF-kappa B , 1995, Molecular and cellular biology.

[24]  G. Nabel,et al.  Regulation of human retroviral latency by the NF-kappa B/I kappa B family: inhibition of human immunodeficiency virus replication by I kappa B through a Rev-dependent mechanism. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  U. Siebenlist,et al.  Activation of NF-kappa B requires proteolysis of the inhibitor I kappa B-alpha: signal-induced phosphorylation of I kappa B-alpha alone does not release active NF-kappa B. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Hiscott,et al.  Constitutive phosphorylation and turnover of I kappa B alpha in human T-cell leukemia virus type I-infected and Tax-expressing T cells , 1995, Journal of virology.

[27]  G. Franzoso,et al.  Human T-cell leukemia virus type I Tax-protein-mediated activation of NF-kappa B from p100 (NF-kappa B2)-inhibited cytoplasmic reservoirs. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A. Baldwin,et al.  Inducible phosphorylation of I kappa B alpha is not sufficient for its dissociation from NF-kappa B and is inhibited by protease inhibitors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[29]  P. Baeuerle,et al.  A proteasome inhibitor prevents activation of NF‐kappa B and stabilizes a newly phosphorylated form of I kappa B‐alpha that is still bound to NF‐kappa B. , 1994, The EMBO journal.

[30]  Tom Maniatis,et al.  The ubiquitinproteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB , 1994, Cell.

[31]  R. Silverman,et al.  Blockage of NF-kappa B signaling by selective ablation of an mRNA target by 2-5A antisense chimeras. , 1994, Science.

[32]  M. Nerenberg,et al.  Transcriptional suppression of the human T-cell leukemia virus type I long terminal repeat occurs by an unconventional interaction of a CREB factor with the R region , 1994, Molecular and cellular biology.

[33]  Aseem Kumar,et al.  Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[34]  M. Yoshida,et al.  Tax protein of human T-cell leukemia virus type I binds to the ankyrin motifs of inhibitory factor kappa B and induces nuclear translocation of transcription factor NF-kappa B proteins for transcriptional activation. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Wainberg,et al.  Virus induction of NF-kappa B/Rel proteins and type I interferon gene expression in myelomonoblastic cells. , 1994, Leukemia.

[36]  A. Pardee,et al.  Cooperative inhibition of NF-kappa B and Tat-induced superactivation of human immunodeficiency virus type 1 long terminal repeat. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Hiscott,et al.  Chronic human immunodeficiency virus type 1 infection stimulates distinct NF-kappa B/rel DNA binding activities in myelomonoblastic cells , 1993, Journal of virology.

[38]  M. Yoshida.  HTLV-1 Tax: regulation of gene expression and disease. , 1993, Trends in microbiology.

[39]  A. Baldwin,et al.  Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation , 1993, Molecular and cellular biology.

[40]  B. Cullen.  Does HIV-1 Tat induce a change in viral initiation rights? , 1993, Cell.

[41]  C. Samuel,et al.  The eIF-2 alpha protein kinases, regulators of translation in eukaryotes from yeasts to humans. , 1993, The Journal of biological chemistry.

[42]  G. Franzoso,et al.  Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Sodroski,et al.  The human T-cell leukemia virus (HTLV) transactivator (Tax) protein. , 1992, Biochimica et biophysica acta.

[44]  D. Brenner,et al.  Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity , 1992, Cell.

[45]  M. Czech,et al.  Phosphorylation of transcriptional factors and cell-cycle-dependent proteins by casein kinase II. , 1991, Current opinion in cell biology.

[46]  G. Englund,et al.  A novel HIV-1 isolate containing alterations affecting the NF-κB element , 1991 .

[47]  N. Sonenberg,et al.  A bulge structure in HIV-1 TAR RNA is required for Tat binding and Tat-mediated trans-activation. , 1990, Disease markers.

[48]  I. Kerr,et al.  Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon , 1990, Cell.

[49]  N. Sonenberg,et al.  Structural requirements for trans activation of human immunodeficiency virus type 1 long terminal repeat-directed gene expression by tat: importance of base pairing, loop sequence, and bulges in the tat-responsive sequence , 1990, Journal of virology.

[50]  D. Baltimore,et al.  A 65-kappaD subunit of active NF-kappaB is required for inhibition of NF-kappaB by I kappaB. , 1989, Genes & development.

[51]  C. Giam,et al.  HTLV-I tax gene product activates transcription via pre-existing cellular factors and cAMP responsive element. , 1989, The Journal of biological chemistry.

[52]  P. Luciw,et al.  Structure, sequence, and position of the stem-loop in tar determine transcriptional elongation by tat through the HIV-1 long terminal repeat. , 1989, Genes & development.

[53]  D. Baltimore,et al.  Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-κB transcription factor , 1988, Cell.

[54]  W. Wachsman,et al.  Binding of host-cell factors to DNA sequences in the long terminal repeat of human T-cell leukemia virus type I: implications for viral gene expression. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[55]  R. Gaynor,et al.  Interactions of cellular proteins involved in the transcriptional regulation of the human immunodeficiency virus. , 1987, The EMBO journal.

[56]  K. Yamaguchi,et al.  Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[57]  M. Yoshida,et al.  Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[58]  John D. Minna,et al.  Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma , 1980, Proceedings of the National Academy of Sciences.

[59]  C. Laurent‐Winter,et al.  N- and C-Terminal Sequences Control Degradation of MAD3/IkBa in Response to Inducers of NF-kB Activity , 1995 .

[60]  W. Ho,et al.  The macrophage and HIV-1. , 1994, Immunology series.

[61]  L. Davis,et al.  Induction of Monocytic Differentiation and NF-IcB-like Activities by Human Immtmodeficiency Virus 1 Infection of Myelomonoblastic Cells By Anne Roulston,*g 1 Mario D'Addario,*S 1 Francois Boulerice,*ll Stephen Caplan,~ll Mark A. Wainberg,*Sll82 and John Hiscott*Sil82 , 1992 .

[62]  A. Fauci,et al.  The role of monocyte/macrophages and cytokines in the pathogenesis of HIV infection. , 1992, Pathobiology : journal of immunopathology, molecular and cellular biology.

[63]  H. Gendelman,et al.  Mononuclear phagocytes as targets, tissue reservoirs, and immunoregulatory cells in human immunodeficiency virus disease. , 1992, Current topics in microbiology and immunology.